Biomarkers for early detection of Alzheimer's disease (AD) and for monitoring treatment response are becoming critically important as novel pharmacotherapeutics emerge. Several candidate biochemical, anatomical, and functional biomarkers have shown promise for identifying disease risk or treatment response potential, but vary in their efficacy and invasiveness. Among these candidate biomarkers, task-activated functional magnetic resonance imaging (fMRI) is a promising approach that is noninvasive, carries little risk, and offers a high potential for identifying persons who may eventually develop AD. The purpose of this investigation is to examine the value of task-activated fMRI in the identification and prediction of disease course in populations at-risk for the development of mild cognitive impairment (MCI) or AD. In specific Aim 1, we propose to examine the 7.0 year longitudinal course of 108 asymptomatic individuals with varying risk for conversion to MCI/AD based on the presence/absence of one or two apolipoprotein-E (APOE) e4 alleles and/or a family history of dementia, and of 24 patients with amnestic MCI (aMCI), a condition strongly associated with conversion to AD. Primary measures include fMRI using a semantic memory activation task involving famous name recognition, neurobehavioral testing, and brain morphometry. We hypothesize that baseline levels of brain activation and longitudinal changes in activation will be the strongest predictor of cognitive decline. In Specific Aim 2, we propose to conduct a 24-week, randomized, double-blind, placebo-controlled, parallel group study of the Exelon(R) [rivastigmine] transdermal patch in 120 aMCI patients who have one or both APOE e4 alleles. Task-activated fMRI will serve as the primary biomarker of treatment efficacy along with neuropsychological testing and brain morphometry as secondary endpoints. We hypothesize that the treatment group will demonstrate a normalization (i.e. reduction) in the task-related neural activation pattern relative to the placebo group. In addition, we predict that change in task-activated fMRI magnitude will demonstrate greater sensitivity to cholinergic modulation than changes in neuropsychological testing and structural MRI. These studies offer the opportunity to determine the role of fMRI as a biomarker for predicting future decline in the latent and prodromal phase of AD as well as for monitoring therapeutic outcome in clinical trials. PUBLIC HEALTH RELEVANCE: The early detection of Alzheimer's disease (AD) is critically important for developing effective therapies designed to delay or prevent neurodegeneration. Several candidate biochemical, anatomical, and functional biomarkers have shown promise for identifying disease risk or treatment response potential, but vary in their efficacy and invasiveness. Among these candidate biomarkers, task-activated functional magnetic resonance imaging (fMRI) is a promising approach that is noninvasive, carries little risk, and offers a high potential for identifying persons who may eventually develop AD. The purpose of this investigation is to examine the value of task-activated fMRI in the identification and prediction of disease course in populations at-risk for the development of mild cognitive impairment (MCI) or AD and for monitoring therapeutic outcome in clinical trials.